The vitamin D metabolic pathway is part of a vital endocrine system that is highly regulated at certain stages and produces metabolites that control the secretion of the parathyroid gland hormones (Beckman, M., and DeLuca, H. (1997) Methods in Enzymol. 282, 200-223; Jones, G., Strugnell, S., and DeLuca, H. (1998) Physiol. Rev. 78, 1193-1231). 1α,25-Dihydroxy vitamin D3, also known as calcitriol (see below), a hormone produced in the vitamin D pathway, regulates phosphate and calcium levels in the blood which in turn control bone mass, the state of bones, and affects cellular differentiation in the skin and the immune system (Armbrecht, H. J., Okuda, K., Wongsurawat, N., Nemani, R., Chen, M., and Boltz, M. (1992) J. Steroid Biochem. Molec. Biol. 43, 1073-1081). In the vitamin D pathway, cytochrome P450s are enzymes that introduce functional groups by hydroxylation, usually at positions 1,25, and 24, of vitamin D3 (Beckman, M., and DeLuca, H. (1997) Methods in Enzymol. 282, 200-223).

1α,25-Dihydroxy vitamin D3 is converted to 1α,24,25-trihydroxy-D3 by a mitochondrial P450 known as CYP24 (Bell, N. H., (1998) J. Bone Miner. Res. 13, 350-35211). CYP24 is induced by 1α,25-dihydroxy-D3 and is found in the kidney as well as other vitamin D target tissues such as the parathyroid cells, keratinocytes, osteoblasts, and enteroctyes (Jones, G., Strugnell, S., and DeLuca, H. (1998) Physiol. Rev. 78, 1193-1231). 1α,25-Dihydroxy vitamin D3 (1,25-D3) has an important role in the antiproliferative and growth regulatory effects on normal and neoplastic cells (for e.g. prostate cancer cells). Clinical use of 1,25-D3 analogs as effective drugs requires antiproliferative and pro-differentiating activities.
Oxime ether analogs of 1α,25-dihydroxy vitamin D3 having a fully saturated D-ring side chain are described in U.S. Pat. No. 6,982,258.
There is a continuing need for synthetic analogs of 1α,25-dihydroxy vitamin D3 that selectively exhibit desirable pharmacological activities but do not exhibit hypercalcemic and other undesirable activities.